1. Field of the Invention
The present invention relates to a process for the preparation of guanine (2-amino-1,9-dihydropurin-6-one), starting from 2,4-diamino-5-formylamino-6-hydroxypyrimidine (DAFHP).
2. Discussion of the Background
As an important intermediate for the synthesis of pharmacologically active compounds, in particular of antiviral active compounds, the nucleic acid base guanine is of great importance. Guanine is needed, for example, as a precursor for acyclovir, which according to DE-A-35 44 461, incorporated herein by reference, is suitable for the therapy of viral infections.
The reaction of 4,5-diaminopyrimidine sulfates with formamide to give the corresponding purines is well-known (Robins et al., J. Am. Chem. Soc. 75 (1953) 263). 2,4,5-Triamino-6-hydroxypyrimidine sulfate (TAHP sulfate) is employed for the synthesis of guanine. According to DE-A-37 29 471, guanine can be obtained by heating a suspension of TAHP sulfate in formamide to up to 200.degree. C. with removal by distillation of the water of reaction formed. A disadvantage in this process is that formamide partially decomposes at the high temperatures needed, which in addition to the formation of carbon monoxide and ammonia, results in colored guanine crude products which necessitate a high expenditure on purification. The necessity to employ the TAHP, which is unstable in free form, in the form of its sulfate causes a high salt load, which is a further disadvantage.
According to EP-A-0 415 028, guanine is obtained by reaction of TAHP sulfate with alkali metal formate and formic acid. Although this process avoids the disadvantages associated with the use of formamide, it also leads, however, to production of an economically and ecologically unfavorable high unavoidable salt load in the form of alkali metal sulfate in the reaction mixture.
In the process based on TAHP sulfate described above, 2,4-diamino-5-formylamino-6-hydroxypyrimidine (referred to as DAFHP below) is passed through as an intermediate, which is reacted in situ to produce guanine.
According to DE-A-41 36 114, guanine can also be obtained starting from isolated DAFHP by heating in formamide to at least 140.degree. C. The ratio of DAFHP to formamide is 1:2 to 1:3. Up to 10% of formic acid can be added to the reaction mixture. The DAFHP employed here is obtained, for example, by a process according to EP-A-0 -267 594, in which 2,4-diamino-6-hydroxy-5-nitrosopyrimidine is catalytically hydrogenated and reacted to give TAHP sulfate. After the hydrogenation, the reaction mixture is treated with formic acid, if appropriate with addition of a mineral acid, in order to obtain DAFHP quantitatively. Although the process described in DE-A-41 36 114 is salt-free, it has, however, the already mentioned disadvantages which accompany the use of formamide (such as decomposition, and expensive purification of the final product). The guanine according to DE-A-41 36 114 is obtained with a purity (HPLC) of less than 98.0%. After purification, losses in yield therefore occur.
Accordingly, there remains a need for a process for producing guanine which overcomes the disadvantages discussed above.